Medical devices are used for myriad purposes on and throughout an animal's body. They can be simple ex vivo devices such as adhesive bandages, canes, walkers and contact lenses or. complex implantable devices including pacemakers, heart valves, vascular stents, catheters and vascular grafts. Implantable medical devices must be biocompatible to prevent inducing life threatening adverse physiological responses between the implant recipient and device.
Cardiovascular disease, specifically atherosclerosis, remains a leading cause of death in developed countries. Atherosclerosis is a multifactorial disease that results in a narrowing, or stenosis, of a vessel lumen. Briefly, pathologic inflammatory responses resulting from vascular endothelium injury causes monocytes and vascular smooth muscle cells (VSMCs) to migrate from the sub endothelium and into the arterial wall's intimal layer. There the VSMC proliferate and lay down an extracellular matrix causing vascular wall thickening and reduced vessel patency.
Cardiovascular disease caused by stenotic coronary arteries is commonly treated using either coronary artery by-pass graft (CABG) surgery or angioplasty. Angioplasty is a percutaneous procedure wherein a balloon catheter is inserted into the coronary artery and advanced until the vascular stenosis is reached. The balloon is then inflated restoring arterial patency. One angioplasty variation includes arterial stent deployment. Briefly, after arterial patency has been restored, the balloon is deflated and a vascular stent is inserted into the vessel lumen at the stenosis site. The catheter is then removed from the coronary artery and the deployed stent remains implanted to prevent the newly opened artery from constricting spontaneously. However, balloon catheterization and stent deployment can result in vascular injury ultimately leading to VSMC proliferation and neointimal formation within the previously opened artery. This biological process whereby a previously opened artery becomes re-occluded is referred to as restenosis.
The introduction of intracoronary stents into clinical practice has dramatically changed treatment of obstructive coronary artery disease. Since having been shown to significantly reduce restenosis as compared to percutaneous transluminal coronary angioplasty (PTCA) in selected lesions, the indication for stent implantation was been widened substantially. As a result of a dramatic increase in implantation numbers worldwide in less selected and more complex lesions, in-stent restenosis (ISR) has been identified as a new medical problem with significant clinical and socioeconomic implications. The number of ISR cases is growing: from 100,000 patients treated worldwide in 1997 to an estimated 150,000 cases in 2001 in the United States alone. ISR is due to a vascular response to injury, and this response begins with endothelial denudation and culminates in vascular remodeling after a significant phase of smooth muscle cell proliferation.
At least four distinct phases of reaction can be observed in ISR: thrombosis, inflammation, proliferation, and vessel remodeling. There is a wide spectrum of conventional catheter-based techniques for treatment of ISR, ranging from plain balloon angioplasty to various atherectomy devices and repeat stenting. One possible method for preventing restenosis is the administration of anti-inflammatory compounds that block local invasion/activation of monocytes thus preventing the secretion of growth factors that may trigger VSMC proliferation and migration. Other potentially anti-restenotic compounds include anti-proliferative agents such as chemotherapeutics including rapamycin and paclitaxel. However, anti-inflammatory and anti-proliferative compounds can be toxic when administered systemically in anti-restenotic-effective amounts. Furthermore, the exact cellular functions that must be inhibited and the duration of inhibition needed to achieve prolonged vascular patency (greater than six months) is not presently known. Moreover, it is believed that each drug may require its own treatment duration and delivery rate. Therefore, in situ, or site-specific drug delivery using anti-restenotic coated stents has become the focus of intense clinical investigation. Once the coated stent is deployed, it releases the anti-restenotic agent directly into the tissue thus allowing for clinically effective drug concentrations to be achieved locally without subjecting the recipient to side effects associated with systemic drug delivery. Moreover, localized delivery of anti-proliferative drugs directly at the treatment site eliminates the need for specific cell targeting technologies.
Angiotensin II (Ang II) has been implicated in the development of restenosis through several mechanisms, and thus control of the renin-angiotensin system (RAS) is a potential target for its prevention. Ang II is produced as a circulating hormone by the angiotensin I (Ang I) converting enzyme (ACE). Stimulation of the angiotensin type 1 (AT1) receptor by Ang II has been shown to be associated with stimulation of cell migration and proliferation in several in vitro and in vivo models including stimulation of extracellular matrix deposition and collagen I, III and IV and fibronectin by VSMCs; stimulation of inflammation; and stimulation of intracellular formation of reactive oxygen species. In addition, AT1 stimulation has been shown to induce changes related to endothelial dysfunction.
Selective AT1 receptor blockade would thus be a potentially beneficial approach as it would inhibit the deleterious effects of AT1 receptor activation. However, rather than targeting AT1 receptor blockade, therapeutic intervention has primarily focused on reducing the production of Ang II by the action of ACE. The effect of ACE inhibitors on the prevention of restenosis has been investigated in two large clinical trials of the ACE inhibitor cilazapril involving more than 2,000 patients. After six months of treatment, no significant differences were seen in the incidence of restenosis between cilazapril and placebo. The inhibition of the conversion of Ang I to Ang II by ACE inhibitors was not successful in these trials and several explanations may therefore be put forward. First, the ACE inhibitor dose may have been too low to obtain sufficient ACE inhibition; high-dose ACE inhibition seems to be more effective than low dose ACE inhibition. Next, the rise in renin and Ang I that occurs when Ang II no longer suppresses renin release may, in part, overcome ACE inhibition. Third, ACE upregulation is known to occur both as a consequence of chronic ACE inhibitor therapy and during the progression of cardiovascular diseases. Finally, in vitro studies have shown that there are alternative enzymes capable of converting Ang I into Ang II. The most important of these is the serine protease chymase.
Compared with ACE inhibitors, angiotensin receptor blockers exert additional effects on the pathophysiological processes which lead to restenosis. Angiotensin receptor antagonists may affect several mechanisms involved in neointimal hyperplasia such as decreasing circulating cytokine and growth factor levels and reducing neutrophil activation. First results of using angiotensin receptor blockers after stent implantation indicated favorable results could be obtained in the prevention of in-stent restenosis through a systemic pharmacological approach (Wilensky R. L. Angiotensin-receptor blockers: Revival of the systemic prevention of restenosis? Cardiovasc. Drugs Ther. 17:63–73, 2003). This VaIPREST trial was the first randomized, placebo-controlled study to have evaluated the effect of an angiotensin receptor blocker on in-stent restenosis in a moderate number of patients. The VaIPREST trial was recently supplemented by the VALVACE trial (Peters S., et al. Valsartan versus ACE inhibition after bare metal stent implantation—results of the VALVACE trial. Int. J. Cardiol. 98:331–335, 2005). Similar to the results of the VaIPREST trial, the VALVACE trial demonstrated an impressive reduction of in-stent restenosis in comparison to ACE inhibition. These initial trials suggest that angiotensin receptor blocker therapy my be effective as an add-on therapy to drug-eluting stent.
Angiotensin-(1-7) (Ang-(1-7)), a heptapeptide biologically active member of the renin-angiotensin peptide family, antagonizes the RAS system at various levels. Being a substrate for ACE, Ang-(1-7) competes with Ang I and bradykinin for degradation, thereby inhibiting Ang II formation and augmenting bradykinin activity. Ang-(1-7) has also been found to block the deleterious actions of Ang II through a noncompetitive blockade of AT1 receptors and direct stimulation of angiotensin type 2 (AT2) receptors. Although ACE inhibitors were originally developed to suppress the formation of Ang II, part of their beneficial effect in cardiovascular diseases may be attributed to the resultant elevation in Ang-(1-7) levels. ACE inhibitor treatment, although having limited effects on the circulating amount of Ang II, increases Ang-(1-7) levels 10–to 25-fold.
Intravenous infusion of Ang-(1-7) inhibited smooth muscle cell proliferation associated with balloon-catheter injury (Strawn W. B. et al. Angiotensin(1-7) reduces smooth muscle growth after vascular injury, Hypertension 33:207–11, 1999). Ang-(1-7) also opposes the mitogenic response to Ang II in cultured VSMCs. Further, Ang-(1-7), through interaction with its recently discovered Ang-(1-7) receptor, has a vasodilatory effect by way of stimulating nitric oxide release.
Human clinical studies on stent-based anti-restenotic delivery have demonstrated excellent short-term anti-restenotic effectiveness. However, side effects including vascular erosion have also been seen. Vascular erosion can lead to stent instability and further vascular injury. Furthermore, the extent of cellular inhibition may be so extensive that normal re-endothelialization will not occur. The endothelial lining is essential for maintaining vascular elasticity and as an endogenous source of nitric oxide. Therefore, compounds that exert localized anti-restenotic effects while minimizing vascular and cellular damage are essential for the long-term success of drug delivery stents. Moreover, it would be beneficial if these compounds would improve vascular endothelial cell function.